1. Field of the Invention
The present invention relates to a process for producing 2-azabicyclo[2.2.1]hept-5-en-3-one (ABH), which is an intermediate in the synthesis of carbocyclic nucleosides that are useful as medicinal agents such as anti-virus agents.
2. Description of the Background
Since carbocyclic nucleosides have a structure in which the oxygen atom of the furanose ring of the nucleoside is substituted with a methylene group and the structure is very similar to a natural nucleoside having a furanose ring, these molecules can act as substrates or inhibitors for various enzymes in living bodies. Further, since the carbocyclic nucleoside has no glycoside bonding, the compound can not be cleaved or split by enzymes such as nucleoside phospholylases and nucleoside hydrases. Since they have different metabolic pathways from natural nucleosides having the furanose ring, they exhibit various physiological activities. For example, carbocyclic adenosine known as Aristeromycin is a sort of carbocyclic nucleoside, which is a metabolite of Streptomyces citricolor and has been noted for its strong cytotoxicity which is different from nucleosides having the furanose ring.
Further, carbocyclic-2,3-dideoxy-2,3-didehydroguanosine, as a sort of carbocyclic nucleoside, has now been developed as an anti-HIV agent (R. Vince et al., Biochem, Biophys. Res. Commun. 156, 1046 (1988)).
ABH is a compound that is most frequently used as an intermediate for the pure chemical synthesis of the carbocyclic moiety of these carbocyclic nucleosides, such as 2 .alpha., 3 .alpha.-dihydroxy-4 .beta.-aminocyclopentanone-1 .beta.-methanol and cis-4-aminocyclopent-2-en-1 .beta.-methanol (R. Vince, et al., J. Org. Chem., 43, 2311 (1978); B. L. Kamm et al., J. Org. Chem., 46, 3268 (1981); W. C. Faith et al., J. Org. Chem., 50, 1983 (1985)).
A method of synthesis of ABH is known in which cyclopentadiene and p-toluenesulfonyl cyanide are subjected to a cycloaddition reaction to form 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene as an intermediate and then removing the toluenesulfonyl group on the 3-position of the intermediate by using acetic acid (J. C. Jagt et al., J. Org. Chem., 39, 564 (1974); R. Vince et al., J. Org. Chem., 43, 2311 (1978)).
However, the process of synthesis process described above has various problems, for example, in that 1+L cyclopentadiene which may be used theoretically in an equimolar amount to p-toluenesulfonyl cyanide has to be actually used in a greatly excess amount of 15 to 35 molar times; 2 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene obtained by the reaction of p-toluenesulfonyl cyanide and cyclopentadiene has to be condensed and removed as lumps from the reaction medium, which then must be pulverized into powder and then reacted with acetic acid; 3+L acetic acid has to be added in a greatly excess amount of 5 to 23 molar times, all at once in order to remove the toluenesulfonyl group at the 3-position by treating 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene with acetic acid, so that an abrupt exothermic reaction has to be controlled; 4+L if the exothermic reaction of item 3+L cannot be controlled satisfactorily and the reaction temperature rises excessively, the desired product, ABH, cannot be obtained at all or is obtainable only in extremely low yields, 5+L solid by-products are formed upon the reaction in the 3+L , which hinder smooth stirring and the reaction does not proceed smoothly; and 6+L a great amount of waste water is formed which increases the burden for treating the same. Therefore, ABH cannot be produced satisfactorily industrially by the synthesis process described above, from the viewpoint of economy and safety.
Under the circumstances described above, effort has now been made to develop a process which is capable of producing ABH in a high purity and a high yield with safety and in good productivity by reacting a sulfonyl cyanide such as p-toluenesulfonyl cyanide with cyclopentadiene under conditions which permit the use of a reduced amount of the reagent and solvent to be used. Previous effort in this area has already produced results, with patent applications having been filed which describe these efforts:
(i) A process for producing ABH by way of a first step of condensing sulfonyl cyanide and cyclopentadiene in a hydrocarbon solvent and then treating the product obtained with water (Japanese Published Unexamined Patent Application No. Hei 5-331139);
(ii) A process for producing ABH by reacting sulfonyl cyanide and cyclopentadiene in water or in a mixed solvent of water and a hydrocarbon (Japanese Published Unexamined Patent Application No. Hei 5-331140);
(iii) A process for producing ABH by reacting benzenesulfonyl cyanide and cyclopentadiene in a mixed solvent of water and a water soluble solvent under pH conditions ranging from 3 to 4 (Japanese Published Unexamined Patent Application No. Hei 8-27110); and
(iv) A process for producing ABH by reacting sulfonyl cyanide and cyclopentadiene in a hydrocarbon solvent to form 3-sulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene as an intermediate product and hydrolyzing the intermediate product by adding a solution of the intermediate product into a mixed solvent of water and a water soluble solvent at a pH ranging from 3 to 7 (Japanese Published Unexamined Patent Application No. Hei 9-165372).
When compared with the existing process described by J. C. Jagt et al. in which ABH is prepared by reacting acetic acid with 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene prepared in turn by the reaction of cyclopentadiene and p-toluenesulfonyl cyanide, the procedures (i)-(iv) described above have various advantages including that:
(a) it is not necessary to use cyclopentadiene in a great excess relative to sulfonyl cyanide; PA1 (b) no troublesome procedure or effort needs to be expended to remove 3-p-toluenesulfonyl-2-azabicyclo[2.2.1]hepta-2,5-diene, which is formed as the intermediate product in a condensed form, pulverizing the same into powder, and then subjecting the powder to a succeeding process step; PA1 (c) since no abrupt exothermic reaction takes places, control of the reaction is easy and results in increased safety; PA1 (d) the yield of the desired product ABH is high; PA1 (e) solid by-products which hinder the stirring during the reaction are formed in comparatively lesser amounts; and PA1 (f) the amount of waste water to be treated is small which moderates the processing burden. PA1 wherein R represents an alkyl group or a phenyl group which may be substituted with cyclopentadiene, and continuously adding the resultant reaction solution to water or a mixed solvent comprising water and a hydrocarbon solvent under the condition that the pH of the present reaction mixture ranges from 4 to 7. PA1 wherein R.sup.1 and R.sup.2 each independently represents a hydrogen atom, an alkyl group or a halogen atom.
Each of the processes (i) and (iv) above is conducted by way of two steps of reacting sulfonyl cyanide and cyclopentadiene in a hydrocarbon solvent in the first step to form 3-sulfonyl-2azabicyclo[2.2.1]hepta-2,5-diene as an intermediate product and then processing the solution of the intermediate product in water in the process (i) or a mixed solvent of water and a water soluble solvent in the process (iv) in the second step to produce ABH.
In these processes, however, it is necessary to handle 3-sulfonyl-2-azabicylo[2.2.1]hepta-2,5-diene, which is relatively unstable. In view of this constraint, room for improvement remains.
On the other hand, each of the processes (ii) and (iii) above is a process by which ABH can be directly produced by reacting sulfonyl cyanide and cyclopentadiene in water or a mixed solvent of water and a hydrocarbon solvent or in a mixed solvent of water and a water soluble solvent in one step. This process is simpler than the two step processes (i) or (iv) above and can be said to be industrially advantageous.
In method (ii), the pH is not controlled during the reaction of sulfonyl cyanide and cyclopentadiene, and it has been found that the pH of the reaction mixture is 3 or less, generally pH 2 to 3, because of the presence of sulfonyl cyanide in the mixture or a sulfinic acid such as, for example, benzenesulfinic acid, which is formed by the reaction. Because of this fact it is difficult to completely prevent deposition of material from the reaction mixture, of solid products such as dimerization products of sulfinic acid such as benzenesulfinic acid, of the likes of, for example, benzenesulfinyl sulfone, which results from the reaction of sulfonyl cyanide and cyclopentadiene, for example, and thus a filtration step for the deposited solid products is required. If deposition of the solid products is to be prevented completely, a great amount of water or hydrocarbon solvent has to be used, which increases the burden on waste water treatment, which leaves room for improvement in the process.
Further, in method (iii) above, sulfonyl cyanide and cyclopentadiene react at a pH ranging from 3 to 4 and it is difficult to completely prevent deposition of dimerization products of a sulfinic acid such as benzenesulfinic acid, of the likes of benzenesulfinyl sulfone, for example, perhaps because a mixed solvent of water and a water-soluble solvent is used as a solvent. Moreover, method (iii) gives a lower yield of ABH than process (ii) described above. A need, therefore, continues to exist for improvement in ABH synthesis.